UFT

UFT

tegafur + uracil

Manufacturer:

Taiho

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Tegafur, uracil.
Description
Each capsule contains tegafur 100 mg and uracil 224 mg. It also contains sodium lauryl sulfate as inactive ingredient.
UFT hard-shell capsule contains white, practically odorless, fine granules and powder having a bitter taste.
Size and Weight: Total Length: 17.6 mm; long diameter (cap): 6.3 mm; short diameter (body): 6 mm; weight: 414.2 mg.
Tegafur is 5-Fluoro-1-[(RS)-tetrahydrofuran-2-yl] pyrimidine-2,4(1H,3H)-dione. It has a molecular formula of C8H9FN2O3; molecular weight of 200.17 and a melting point of 166-171°C. It occurs as a white crystalline powder and is soluble in methanol; sparingly soluble in water and ethanol (95%) and slightly soluble in diethyl ether. It dissolves in dilute sodium hydroxide test solution.
Uracil is 2,4(1H,3H)-pyrimidine-dione. It has a molecular formula of C4H4N2O2; molecular weight of 112.09 and a melting point of approximately 335°C (decomposition). It occurs as a white crystal or crystalline powder, free of odor or taste. It is slightly soluble in water, very slightly soluble in methanol, ethanol (95%) and acetone; and practically insoluble in ethyl acetate and chloroform.
Action
Antimetabolic agent.
Pharmacology: Antitumor Activity: UFT has effects to inhibit the growth of tumors eg, Walker-256 carcinosarcoma, Yoshida sarcoma, ascites hepatoma (in rats), Sarcoma-180, Ehrlich carcinoma, Lewis lung carcinoma and B-16 melanoma (in mice) transplanted SC. It also has effects to inhibit the growth of human cancers eg, gastric, breast and pancreatic when transplanted SC to nude mice. UFT also has survival effects in animals (mice) bearing L-1210 transplanted leukemia.
Mechanism of Action: The antitumor activity of UFT is based on 5-fluorouracil (5-FU) that appears gradually in the body via the transformation of tegafur.
The action mechanism of 5-FU is considered to be inhibition of DNA synthesis resulting from the antagonistic effect of the active metabolite FdUMP acting upon dUMP to inhibit thymidylate synthase and RNA-function disorders resulting from the incorporation of FUTP to RNA (in vitro).
Uracil, when combined with tegafur, enhances tegafur's antitumor activity. Because 5-FU degradation is depressed by the difference of affinities to phosphorylating or degradating enzymes between 5-FU and uracil, concentrations of 5-FU and its phosphorylated active metabolites can be highly maintained in tumor tissues (in vitro).
Clinical Studies: Summarized were the results of clinical trials of UFT (corresponding to 300-600 mg as tegafur in 2 or 3 divided doses/day) on the basis of oral administration. In a total of 699 patients evaluable for efficacy, the response rate was 23.3% (163/699 patients).
The response rate for each cancer was as follows: See Table 1.

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Pharmacokinetics: Three capsules of UFT (corresponding to 300 mg as tegafur) were orally administered to cancer patients and the blood levels of tegafur, 5-FU and uracil were determined. The mean blood level of tegafur was a maximum of 13.7±1.1 mcg/mL at 2 hrs, which then fell gradually to 3.6±0.8 mcg/mL at 24 hrs post-administration. The mean blood levels of 5-FU and uracil were a maximum of 0.21±0.094 mcg/mL and 3±1.8 mcg/mL at 30 min, respectively. The level of 5-FU then fell to 0.05±0.019 mcg/mL at 3 hrs and the level of uracil fell to 0.3±0.23 mcg/mL at 6 hrs after UFT administration.
The levels of 5-FU in the blood, tumor tissues and normal tissues adjacent to the tumors post-administration of UFT were comparatively determined, from which it was realized that the 5-FU level in the tumors was the highest.
It has been reported that CYP2A6 is the major human liver cytochrome P450 isoenzymes involved in the metabolic transformation of tegafur to 5-FU (in vitro).
Indications/Uses
Remission of subjective and objective symptoms in the following cancers: Head and neck, gastric, colorectal, hepatocellular, gallbladder or bile duct, pancreatic, lung, breast, bladder, prostatic and uterine cervical.
Dosage/Direction for Use
Usually, 300-600 mg orally administered as tegafur in 2 or 3 divided doses/day.
Uterine Cervical Cancer: Usually, 600 mg orally administered as tegafur in 2 or 3 divided doses/day. Even in combined use with other antineoplastic agents, UFT should be administered as described previously.
Conversion Table for UFT: See Table 2.

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Contraindications
History of severe hypersensitivity to the ingredients of UFT.
Patients receiving treatment with tegafur, gimeracil and oteracil potassium combination product or within 7 days after withdrawal of this combination product (see Interactions).
Use in pregnancy & lactation: UFT is contraindicated to patients who are or may be pregnant. (It has been reported that pregnant women treated with UFT have been delivered of neonates with malformation.) Teratogenicity is also reported in animal experiments. (Skeletal anomalies and retarded ossification have been observed in fetal rats.)
When UFT is administered to lactating mothers, breastfeeding should be discontinued. [Transfer to milk has been reported in animal (rats) experiments.]
Warnings
In as much as there may occur severe hepatic disorders eg, fulminant hepatitis, patient's hepatic functions should be monitored closely by periodic (at least once a month, particularly for the first 2 months after the start of administration) hepatic function tests to detect hepatic disorder early. Close monitoring should be given to detect possible malaise accompanied by anorexia, which is thought to be a sign or subjective symptom of hepatic disorder. If jaundice (yellow ocular coloring) appears, immediately discontinue administration and take proper measures.
UFT should not be combined with tegafur, gimeracil and oteracil potassium combination product because the concomitant administration with this combination product may cause adverse reactions eg, serious blood dyscrasia (see Interactions).
Special Precautions
Patients with bone marrow depression (bone marrow depression may be aggravated); hepatic disorder or a history of hepatic disorder (hepatic disorder may be aggravated); renal disorder (exaggeration of adverse reactions may occur); infectious disease (infectious disease may be aggravated as a result of potential bone marrow depression); heart disease or a history of heart disease (symptoms may be aggravated); gastrointestinal ulcer or hemorrhage (symptoms may be aggravated); abnormal glucose tolerance (abnormal glucose tolerance may be aggravated); varicella (fatal systemic damage may occur).
Because there may occur serious adverse reactions eg, bone marrow depression, patient's hematological, hepatic and renal functions should be closely monitored by periodic (at least once a month, particularly for the first 2 months after the start of administration) clinical examinations. If any abnormal findings are observed, proper measures eg, dose reduction or discontinuation, should be taken.
If dehydration secondary to severe enteritis occurs, take proper measures eg, fluid replacement (see Adverse Reactions).
Care should be taken to avoid the appearance or aggravation of infection or bleeding tendency.
A minimum washout period of 7 days must be provided when UFT is used after withdrawal of tegafur, gimeracil and oteracil potassium combination product (see Interactions).
It has been reported that acute leukemia (in some cases accompanied with preleukemic phase) or myelodysplastic syndrome (MDS) have occurred in patients treated with a fluorouracil-group drug in combination with other antineoplastic agents.
It has been reported that deficiency of dihydropyrimidine dehydrogenase (DPD), a catabolic enzyme of fluorouracil, exists in an extremely rare patients and if fluorouracil-group drugs are administered to such patients, serious adverse reactions (eg, stomatitis, diarrhea, blood dyscrasia and neuropathy) may occur in the early stages of administration.
Use in children: Administration to children should be conducted with great caution, paying attention to appearance of adverse reactions.
Administration to children and reproducible patients should be performed with consideration of potential gonadic effects.
The safety of UFT in low birth weight infants, neonates, infants or children has not been established.
Use in the elderly: Care should be exercised in administration to elderly patients whose physiological functions are generally in a diminished state.
Use In Pregnancy & Lactation
UFT is contraindicated to patients who are or may be pregnant. (It has been reported that pregnant women treated with UFT have been delivered of neonates with malformation.) Teratogenicity is also reported in animal experiments. (Skeletal anomalies and retarded ossification have been observed in fetal rats.)
When UFT is administered to lactating mothers, breastfeeding should be discontinued. [Transfer to milk has been reported in animal (rats) experiments.]
Adverse Reactions
Of 29,586 patients evaluable for adverse reactions at the time of approval, at the end of re-examination and in the subsequent post-marketing surveillance (for capsules, fine granules and E granules), the incidence of adverse reactions including changes in laboratory values was 14.8% (4388 patients). The most frequent adverse reactions were digestive symptoms eg, anorexia (3.8%), nausea (2.4%), vomiting (1.1%) and diarrhea (1.5%), blood dyscrasias eg, leukopenia (3.1%), thrombocytopenia (1.1%) and anemia (0.8%), hepatic disorder (1.8%) and pigmentation (0.7%).
Clinically Significant Adverse Reactions: Blood dyscrasias eg, bone marrow depression and hemolytic anemia: Since pancytopenia (<0.1%), agranulocytosis (<0.1%) (symptoms: Fever, sore throat and malaise), leukopenia (3.1%), thrombocytopenia (1.1%), anemia (0.8%), bleeding tendency (<0.1%) and hemolytic anemia (<0.1%) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, proper measures eg, discontinuation of administration, should be taken.
Severe hepatic disorder eg, fulminant hepatitis (see Warnings).
Hepatic Cirrhosis: Since hepatic cirrhosis may occur without remarkable increase in AST (GOT) and ALT (GPT) in patients with long-term administration, the patient's conditions should be monitored closely. If prolonged prothrombin time, decreased albumin, decreased cholinesterase or thrombocytopenia are observed, administration should be discontinued.
Dehydration: Since severe diarrhea may occur and dehydration may develop, the patient's condition should be monitored closely. If any such symptoms are observed, discontinuation of administration and proper measures eg, fluid replacement, should be taken.
Severe Enteritis: Hemorrhagic enteritis, ischemic enteritis or necrotic enteritis may occur. Accordingly, patients should be monitored closely. If severe symptoms eg, abdominal pain and diarrhea occur, discontinuation of administration and proper measures should be taken.
Severe Psychoneurologic Disorder eg, Leukoencephalopathy: Since leukoencephalopathy (early symptoms: Dizziness/lightheaded feeling, numbness, impaired tongue movement, gait tripping and forgetfulness), tetraplegia, extrapyramidal symptoms (<0.1%), sensory disturbance (<0.1%), consciousness disturbance, disturbed orientation (<0.1%), somnolence (<0.1%), hypomnesia (<0.1%), speech disorder (<0.1%), gait disturbance (<0.1%) and urinary incontinence may occur, the patient's condition should be monitored closely, and if any such symptoms are observed, administration should be discontinued.
Angina Pectoris, Myocardial Infarction, Arrhythmia: Since angina pectoris (<0.1%), myocardial infarction and arrhythmia (including ventricular tachycardia) may occur, the patient's condition should be monitored closely. If chest pain, syncope, breathlessness, palpitation or abnormal ECG appear, discontinuation of administration and proper measures should be taken.
Acute Renal Failure, Nephrotic Syndrome: Since acute renal failure (<0.1%) and nephrotic syndrome (<0.1%) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, discontinuation of administration and proper measures should be taken.
Anosmia: Since dysosmia (<0.1%) may occur (particularly in patients receiving long-term administration), and anosmia may develop, the patient's condition should be monitored closely. If any abnormal findings are observed, proper measures eg, discontinuation of administration, should be taken.
Interstitial Pneumonia: Since interstitial pneumonia (<0.1%) (early symptoms: Coughing, shortness of breath, dyspnea and fever) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, discontinuation of administration and proper measures eg, chest x-ray examination and administration of adrenocortical hormone, should be taken.
Acute Pancreatitis: Since acute pancreatitis may occur, the patient's condition should be monitored closely. If abdominal pain or increased serum amylase levels appear, discontinuation of administration and proper measures should be taken.
Severe Stomatitis, Gastrointestinal Ulcer and Gastrointestinal Hemorrhage: Since severe stomatitis (incidence unknown), gastrointestinal ulcer (0.1%) and gastrointestinal hemorrhage (<0.1%) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, discontinuation of administration and proper measures should be taken.
Muco-Cutaneo-Ocular Syndrome (Stevens-Johnson Syndrome) and Toxic Epidermal Necrolysis (Lyell Syndrome): Since muco-cutaneo-ocular syndrome and toxic epidermal necrolysis (incidence unknown) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, discontinuation of administration and appropriate measures should be taken.
Other Adverse Reactions: Since the following adverse reactions may occur, if any abnormal findings are observed, proper measures eg, dose reduction or discontinuation of administration, should be taken. If hypersensitivity is noted, UFT should be withdrawn. (See Table 3.)

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Drug Interactions
Contraindications for Co-Administration: UFT should not be co-administered with the following drugs: See Table 4.

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Precautions for Co-Administration: UFT should be administered with care when co-administered with the following drugs: See Table 5.

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Caution For Usage
For drugs that are dispensed in a press-through package (PTP), the patient should be instructed to remove the drug from the package prior to use. It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, resulting in severe complications eg, mediastinitis.
Storage
Store below 25°C.
ATC Classification
L01BC53 - tegafur, combinations ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
Presentation/Packing
Cap (opaque, white cap and white body imprinted with 'TC434') 12 x 10's.
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